Mammalian bombesin-like neuropeptides, gastrin releasing peptide (GRP) and neuromedin B (NMB), mediate a diverse range of biological responses in normal tissues, and stimulate the growth of some lung, pancreatic, and prostate carcinomas. Our laboratory cloned and characterized three structurally and pharmacologically distinct human bombesin receptors: the gastrin- releasing peptide receptor (GRP-R, or bb2); the neuromedin B receptor (NMB-R, or bb1); and bombesin receptor subtype 3 (BRS-3, or bb3). All three receptors are members of the G-protein coupled receptor superfamily, coupling to heterotrimeric G-proteins that activate phospholipase C. Several advances in our understanding of the function and regulation of these receptors has occurred within the last year: (1) we have used gene targeting strategies to create mice which lack the GRP-R, and progressed in our efforts to generate similar mice that lack BRS-3. Mice lacking GRP-R do not exhibit bombesin-induced satiety, implicating the GRP-R as a regulator of appetite. As these mice age, we hypothesize that GRP-R targeted mice will become obese. (2) We have developed a protocol that allows us to generate uncoupled receptors embedded in a normal biological membrane. This preparation allows us to reconstitute coupling to purified G- proteins, examining the selectivity and enzymology of receptor- catalyzed nucleotide exchange on heterotrimeric GTP-binding proteins. Using this assay, we show that phosphorylation of serines and threonines in the C-terminal domain of the GRP-R inhibits coupling to heterotrimeric G-proteins thereby establishing that ligand-stimulated receptor phosphorylation is the switch that turns off receptor signalling.